1. Field of the Invention
This invention relates in general to metal-containing compositions which mimic the skeletal structure of asteroid, and more particularly to such compositions in which a selected metal ion is integrated into a tertiary or quaternary center of a steroid skeleton structure by occupying a position in the steroid structure previously occupied by a carbon atom and which are useful in delivering a metal to a targeted site for diagnostic or therapeutic purposes.
2. Description of Background Art
The development of radiopharmaceuticals capable of delivering a selected metal ion to a targeted biological site has been the focus of much research in the biological and medical fields. Radiopharmaceuticals have, in fact, been developed that are capable of being targeted to a specific site and have found use in radioimaging, radiotherapy, and as a tool for the prognosis of disease. In recent years the use of radiopharmaceuticals to diagnose, image and/or provide therapy for tumors has been increasing. Recent studies have also shown that steroid receptors in tumor cells, such as those found in breast cancer and prostate cancer, may provide important prognostic information on the status of the tumor and in selecting an effective course of treatment. Rayter, Z., "Steroid Receptors in breast cancer," Br. J. Surg. (1991) Vol. 78, pp.528-535; Donegan, W. L., "Prognostic Factors," Cancer Supplement (1992) Vol. 70, No. 6, pp. 1755-1764; Wilding, G., "The Importance of Steroid Hormones in Prostate Cancer," Cancer Surveys Volume 14: Growth Regulation by Nuclear Hormone Receptors, (1992) pp.113-130. It would be considered an advance in the art if a radiopharmaceutical that could advantageously exploit the presence of steroid receptors on a tumor cell or other biological tissue were available.
One method by which steroid receptors on tumors or other biological tissues could be utilized would be to attach a radiolabelled metal complex to the steroid molecule which binds to the receptor. Various effector molecules, such as drugs, enzymes, chemotoxins, probes, and the like, have been prepared for targeted delivery to a biological site bycovalently attaching a receptor specific carrier molecule, such as an antibody or a peptide, thereto. Halpern et al., Diagnostic Imaging, 1983, 40; Hnatowich et al., Science, 1983, 220, 613. This approach has been referred to as an "external bifunctional" approach and has found some success. It has also been found, however, that if the carrier is a small molecule, i.e. one having a molecular weight of less than about 500 Daltons, the attachment of effector molecules often destroys the receptor binding capability of the carrier molecule. Steroids are small molecules, typically having a molecular weight of around 400 Daltons, and the covalent attachment of a radioactive metal complex to the steroid may obstruct the ability of the steroid to bind to the receptor. Thus, any steroid based radiopharmaceutical should be one that does not adversely affect the binding properties of the steroid. Moreover, an effective steroid-based radiopharmaceutical should maintain the relative size, shape and structure of the steroid molecule.
Others have attempted to prepare a radionuclide complex that is intended to mimic asteroid. In Chi and Katzenellenbogen, J. Am. Chem. Soc., (1993) 115, pp. 7045-7046, heterodimeric bis-bidentate aminothiol complexes of technetiumand rhenium have been prepared that purportedly more closely resembled the size and shape of asteroid molecule. The complexes described by Chi and Katzenellenbogen do not, however, incorporate a radionuclide into the perhydrocyclopentanophenanthrene ring system of the typical steroid structure. Thus, the Chi and Katzenellenbogen approach is one that attempts to combine known ligands in a manner that approximates the size and shape of asteroid or other biomolecule, but that does not use the basic structure of the biomolecule as the template.
Another approach that has been utilized to provide biomolecule mimics is referred to as an "internal bifunctional" approach which incorporates the selected ion directly into the molecular framework of the carrier molecule in such a manner that the resulting structure will be topologically similar to the original molecule. This approach, which is primarily inspired by the fact that antibodies, enzymes, and receptors are multispecific, has been used to prepare opiate alkaloid mimics and is described in my co-pending U.S. application filed on Dec. 6, 1991 having Ser. No. 07/804,852, now U.S. Pat. No. 5,330,737, the entirety of which is herein incorporated by reference hereto. Heretofore, however, the use of an internal bifunctional approach for the preparation of steroid-based radiopharmaceuticals has not been disclosed or suggested. It would be desirable, therefore, to provide metal containing steroid mimics that incorporate a selected metal ion into the structure of a steroid by an internal bifunctional approach and ligands useful in the preparation of such steroid mimics.